1. In utero Exposure to β-2-adrenergic Receptor Agonists and ADHD/ASDs in Children
Hong Liang MD, Ph.D
Department of Epidemiology and Social Medicine
Shanghai Institute of Planned Parenthood Research, China

2. Childhood neuropsychiatric disorders
Attention-Deficit/Hyperactivity Disorder (ADHD)
Persistent pattern of inattention and/or hyperactivity-impulsivity , 5%
Autism spectrum disorders (ASDs)
Persistent deficits in social communication and social interaction, 1‰
Environmental risk factors: maternal stress, lead and polychlorinated biphenyls, and prescribed drugs ( Acetaminophen)

3. β-2-adrenergic receptor agonist (β2AA)
Mainstream medication for asthma treatment
Poorly controlled asthma during pregnancy: increased risks of preeclampsia, preterm birth, low birth weight, and mortality.
β2AA can cross the human placenta and stimulate beta-2- adrenergic receptor
Maternal use of β2AA was reported to be associated with affected cognitive performance and motor development
Few studies on the association between maternal β2AA use and ADHD/ASDs.

4. Objective
To examine the association between prenatal exposure to β2AA and the risk of ADHD and ASDs in offspring

5. Data source Danish national register data
Danish Civil Registration System (CRS)
Danish Medical Birth Register
Danish Integrated Database for Longitudinal Labour Market
Danish National Prescription Registry
Danish National Patient Registry
Danish Psychiatric Central Register
A unique personal identification ensures accurate linkage between all registers
A cohort of 672,265 children were established between 1998 and 2007.

6. Study design and exposure window
During pregnancy
Cases
30 days before Conception
Conception
Birth
Non-cases
Follow-up period
Outcome: ADHD, ASDs
Exposure period
Exposure: Maternal β2AA prescription

7. Danish Prescription Registry
Exposure: maternal β2AA prescription
The Antomical Therapeutic Chemical classification (ATC) codes: R03AC or R03CC
Outcome:
ADHD (ICD10 F90)
ASDs (ICD10 F84.0, .1, .5, .8)
Danish Prescription Registry
Danish National Patient Registry
Danish Psychiatric Central Register

8. Log-linear poisson regression was used to estimate incidence rate ratios (IRR) and 95% confidence interval (CI) of ADHD/ASDs.
Covariates: sex, year of child birth, birth order, paternal age at child birth, maternal age at child birth, maternal education, maternal smoking during pregnancy, maternal socioeconomic status, and family history of psychiatric disorders.
Danish Medical Birth Register
Danish Integrated Database for Longitudinal Labour Market

9. Results In utero exposure to β2AA and the risk of ADHD
In utero exposure to β2AA and the risk of ASDs
Liang H, Chen J, Miao M, Christensen J, Dalsgaard S, Yuan W, et al. In utero exposure to beta-2-adrenergic receptor agonist and attention-deficit/hyperactivity disorder in children. Eur Child Adolesc Psychiatry
Su X, Yuan W, Chen J, Miao M, Olsen J, Pedersen LH, et al. Prenatal exposure to beta2-adrenoreceptor agonists and the risk of autism spectrum disorders in offspring. Pharmacoepidemiology and drug safety. 2017;26(7):812-8.

10. 1. Prenatal exposure to β2AA and ADHD
The percentage of babies born to mothers with β2AA usage during pregnancy: 3.8%
The incidence rate of ADHD: 20.5/10,000 person-years
The median age at ADHD diagnosis: 8.1
-- Is β2AA usage associated with increased risk of ADHD?

11. β2AA usage was associated with a 1.30-fold increased risk of ADHD
Table 1. Incidence rate ratios (IRRs) of ADHD in children following maternal β2AA Use
β2AA usage was associated with a 1.30-fold increased risk of ADHD
Is the association attributed to β2AA use or the underlying indication?

12. Definition of extended exposure window
With indication but no drugs
With indication and drugs
During pregnancy
Both
Before pregnancy
Non-cases
Conception
cases
Birth
2-year
Children born to mothers who had redeemed a β2AA prescription only during pregnancy
are expected to have higher risk compared with only before pregnancy if β2AA did increase
the risk of ADHD

13. Table 2. Incidence rate ratios (IRRs) of ADHD in children following maternal β2AA Use

14. Is the association attributed to β2AA Use ?

15. Is the association gender specific?

16. Table 4. Incidence rate ratios (IRRs) of ADHD following maternal β2AA Use stratified by child sex

18. Sensitivity analyses Stratified analyses Similar results were observed
year of child birth
parental history of psychiatric disorders
Similar results were observed

19. 2. Prenatal exposure to β2AA and ASDs
The incidence rate of ASD: 12/10,000 person-years
The median age at ASDs diagnosis: 7.0 years

20. Table 1. Association between maternal use of β2AA and the risk of ASDs in the offspring according to timing of drug use

21. Table 2. Association between maternal use of β2AA and the risk of ASDs among children of asthmatic mothers

22. Table 3. The association between maternal use of β2AA and the risk of ASDs stratified by sex

23. Summary
Increased risk of ADHD and ASDs following in utero exposure to β2AA
Maternal β2AA usage before pregnancy has similar risk
No association was observed among children whose mother had a history of asthma
The increased risk may be explained by the underlying disorders or associated pathological conditions, instead of the effect of β2AA

24. Strength
Large sample size, including all singletone children born alive, with nearly complete follow-up
adequate power
less selection bias
Re-define exposure
Potential confounders control

25. Limitation The discrepancy between prescription and actual usage
Children with ADHD/ASDs diagnosed outside the hospital system may not be recorded in the register

26. Team members
Hong Liang, Maohua Miao, Jianping Chen & Wei Yuan, Key Lab of Reproductive Regulation of NPFPC, SIPPR, China.
Jiong Li & Jorn Olsen, Department of Clinical Epidemiology, Aarhus University Hospital, Denmark.
Jakob Christensen, Department of Neurology, Aarhus University Hospital, Denmark
Lars Henning Pedersen, Department of Clinical Medicine, Obstetrics and Gynecology, Aarhus University, Denmark
Soren Dalsgaard, National Center for register-based Research, Aarhus University, Denmark

27. Thank you!

31. Does the accompanied medication play any role in the association?
Does dosage of β2AA usage matter?